MicroRNA‐145 induces the senescence of activated hepatic stellate cells through the activation of p53 pathway by ZEB2. Issue 5 (27th November 2018)

• Record Type: Journal Article
• Authors: Yang, Junfa; Lu, Yuchen; Yang, Peipei; Chen, Qingfeng; Wang, Yang; Ding, Qi; Xu, Tao; Li, Xiaofeng; Li, Changyao; Huang, Cheng; Meng, Xiaoming; Li, Jun; Zhang, Lei; Wang, Xiao
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 5(2019:May)
• Page Start: 7587
• Page End: 7599
• Publication Date: 2018-11-27
• Subjects: HSCs senescence -- liver fibrosis -- mi‐145 -- p53 -- SA‐β‐Gal; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.27521
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA‐145 (miR‐145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E‐box binding homeobox 2 (ZEB2). In addition, overexpression of miR‐145 and p53 led to upregulation of the number of senescence‐associated β‐galactosidase‐positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α‐smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR‐145 specifically targeted the 3′‐untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E‐box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR‐145‐ZEB2‐p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis. Abstract : MicroRNA‐145 (miR‐145) exerts its functions by targeting zinc finger E‐box binding homeobox 2 (ZEB2) depended on p53 manner. Schematic representation of the proposed mechanism. Transcription of miR‐145 gene increases the expression of mature miR‐145 which targets the 3′‐untranslated regions of ZEB2 to suppress its translation. Reduced expression of ZEB2 can no longer effectively inhibit p53 transcription factors, thereby accelerating the expression of p53. Ultimately, the increased level of p53 inhibits cell cycle progression and promotes the senescence of activated hepatic stellate cells, thereby inhibiting liver fibrosis.